PROJECT SUMMARY RNA is a validated target for drug design, both as therapeutic and as a target. Targeting specific RNA, such as rRNA which are involved in proliferation and survival of bacteria is a promising approach. We are developing fast and low cost methods to screen sequence-specific small molecules for novel anti-ribosomal activities. We will construct sequence-specific chemically modified ribosomal targeting oligomers that can be effectively delivered inside the cell, addressing the key objective of PAR-17-036 (to generate new technologies and products for delivering nucleic acids into cells and tissues for the purpose of treatment or prevention of human disease). Complexes between ribosomal components will be exploited as targets for small molecule drug libraries that-inactivate the ribosome. NUBADs unique experimental approaches and technologies will allow us to target ribosomal regions not previously explored for susceptibility against microbial targets. The work proposed here, a multidisciplinary effort encompassing solid-phase organic synthesis, oligonucleotide delivery, RNA targeted screening, antimicrobial activity, and in vivo efficacy studies describes the development of sequence-specific cell permeable binders of rRNA. The success of the proposed work would be a significant addition to currently available ribosome-specific approaches in drug development. We propose using a small rRNA target sequences to design conjugates that can be employed to inhibit microbial growth, opening possibilities for developing sequence- specific RNA targeted therapeutics.